NL8203768A - PROCESS FOR THE PREPARATION OF VINCAMINIC ACID ESTERS. - Google Patents

Description

N / 31.133-Kp / Pf / vdM * * - 1 -

Process for the preparation of vincamic acid esters.

The invention relates to a new process for the preparation of vincamic acid esters. More particularly, the invention relates to a new process for the preparation of racemic and optically active vincamic acid esters of formula 1 of the formula sheet, wherein 1 2 R and R independently represent alkyl of 1-6 carbon atoms, as well as 14- epiming these compounds.

According to the invention, an octahydroxndolo-2,3-a-quinololizine oxime of formula 2 of the formula sheet, wherein R and R have the above meanings, is reacted with an aqueous solution of sulfuric acid or salts thereof, at at a temperature of 80-110 ° C and the resulting 14-epimer mixture is epimerized or separated in a manner known per se and, if desired, the racemic vincamic acid esters are separated into their antipodes.

X 6

In the definition of R and R, the term "alkyl of 1-6 carbon atoms" is used to denote straight or branched alkyl groups of 1 to 6 carbon-20 atoms, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.

The compounds of formula 1 are known and show pharmaceutical activity. In particular, the also naturally occurring (+) - vincamic acid methyl ester and the (+) - vincamine are potent cerebral vasodilators.

According to U.S. Pat. No. 3,770,724, the racemic compounds of formula 1 are prepared from the corresponding racemic octahydroindolo / 2,3-aquinololine esters by four-step synthesis. The yields of the subsequent reaction stages are 71%, 61%, 21% and resp. 85%, while the total yield is only 7.7%.

Optically active compounds of the formula 1 can be used according to Helv. Chim. Acta £ 0,1801 (1977) are prepared with a four-step synthesis. Here the subsequent reaction steps can be carried out with the following yields: 8203768% * * - 2 - 83%, 68% and for the last two steps 34%. Accordingly, the total yield is 19%.

By a method described in Hungarian Patent 175,656, the yield of the last two steps of the latter synthesis can be improved to 42% and thus the calculated total yield for the four subsequent reaction steps can be increased to 24%. However, side reactions such as ester hydrolysis, cleavage of water, etc. may occur during the reaction.

All the above-mentioned processes have the disadvantage that they comprise a relatively large number of reaction steps, resulting in a rather low (maximum 24%) total yield.

It has now been quite surprisingly found that starting from the compounds of the formula II, the compounds of the formula I can be prepared efficiently in a single reaction step. Taking into account that the compounds of formula II are prepared from the corresponding octahydroindolo / 2,3-a7 "quinolizine esters according to Hungarian patent application 1753/81, the number of reaction steps required has been reduced from four to two when starting from the same starting material . On the other hand, under the reaction conditions employed, the undesired side reactions, e.g., ester hydrolysis and splitting off of water, can be effectively suppressed, resulting in a significant increase in yield.

As mentioned above, the compounds of formula II can be prepared starting from octahydroindolo / 2,3-§7 "quinolizine esters by reaction with tert-butyl nitrite in an aromatic hydrocarbon solvent and then with an alkali metal tert alcoholate and possibly an aprotic dipolar solvent (Hungarian patent application 1753/81), in 80% yield.

The sulfuric acid salts used as reagents in the process of the present invention may be added to the reaction mixture, for example, in one of the following forms: alkali metal pyrosulphite and water; alkali metal pyrosulfite, water and concentrated sulfuric acid; alkali metal pyrosulfite, water and acetic acid; alkali metal hydroxide, water and sulfur dioxide; an alka- 8203768 4-3- '.

limetal salt, e.g. sodium acetate, water and sulfur dioxide; an aqueous solution of sodium sulfite and concentrated sulfuric acid? an alkali metal salt, eg sodium acetate, concentrated sulfuric acid and sulfur dioxide, etc. In this context, for example, as an alkali metal, sodium or potassium can be used.

The reaction is preferably carried out at a pH between 3.5 and 7. The pH value can be adjusted using any organic or inorganic acid. In view of the 10 solubility ratios, sulfuric acid and acetic acid are preferred.

The reaction is carried out at a temperature of 80-110 ° C, preferably 85-95 ° C, under atmospheric pressure or an overpressure of 0.1-0.5 atm.

The process according to the invention provides a 14-epimer mixture which can be epimerized with an alkali metal alcoholate in a manner known per se, or whose epimers can be separated using suitable solvents.

In the starting compounds of formula 2, 2 can represent the R group in the 1 position and the 12b hydrogen atom in mutual cis- (a, a or β, β) or trans (α, β or $, a) ration. This configuration does not change during the reaction, i.e. remains the same in the final products.

Starting from racemic compounds of formula 2, racemic compounds of formula 1 are obtained, while optically active starting materials lead to optically active end products. If desired, a racemic final product can be cleaved into its antipodes by a known method.

The main advantage of the new process according to the invention consists in the fact that by reducing the number of reaction steps required from four to two (starting from the same starting material), a 2.5 to 35 fold increase in yield is obtained. With regard to industrial application, a further advantage is that the by-products, which may be formed, can be converted into the corresponding pharmaceutically active apovincamic acid esters.

The invention is now further illustrated by the following examples, which serve to illustrate and not limit the present invention.

5 COMPARATIVE EXAMPLE

- (-) - 1 & - {(21-methoxycarbonyl-2'-hydroxyimino) - ethyl7-1a-ethyl-1,2,3,4,6,7,12,12ba-octahydroindolo / 2,3-aquinololizine and its hydrochloride.

To 34 g (0.1 mol) (-) - 1β- (2'-methoxycarbonyl-ethyl) -loiethyl-1,2,3,4,6,7,12,12ba-octahydroindoloi / 2,3 -a7 ”quinolizine, 20 ml of absolute toluene, a 55-60% toluene solution of 30 ml of tert-butyl nitrite and then 17 g (0.15 mol) of potassium tert-butylate were added. The mixture was stirred at 25-30 ° C for 20 min, 150 ml absolute methanol 15 was slowly added and the mixture was stirred at 40 ° C for 3 h. The reaction mixture was then cooled to 20 ° C, acidified to a pH = 1 with concentrated hydrochloric acid, 50 ml of water was added and the mixture was stirred at + 5 ° C for 2 h. The precipitate was filtered off, the KCl was washed with water and the precipitate was dried. 32.5 g (80%) of the title compound hydrochloride were obtained, which melted under decomposition at 265-272 ° C.

57 ° (c = 1, DMF).

From the resulting hydrochloride, the free base was prepared by suspending the salt in 80 ml of methanol and adding a mixture of 25 ml of 25% aqueous ammonium hydroxide solution and 40 ml of water dropwise with stirring.

After stirring for 1 h, it was cooled to 10 ° C, filtered, washed with water and dried. 24-25 g of the title compound were obtained, which melted at 208-210 ° C.

/ Α7β ° = -62 ° (c = 1, DMF).

EXAMPLE I (+) - vincamine

A mixture of 22 g (0.06 mol) (-) - la-ethyl-13-35 (21-methoxycarbonyl-2'-hydroxyiminoethyl) -1,2,3,4,6,7,12,12ba-octahydroindolo 2,3-a7-quinolizine (Hungarian patent application 1753/81, 20 ml of acetic acid, 100 ml of water and 12 g of sodium pyrosul bike was stirred at 90-92 ° C for 6 h. It was left 8203768-5.

Cool the reaction mixture and adjust its pH to 9 using concentrated aqueous ammonium hydroxide solution. The alkaline solution was extracted with two 60 ml portions of dichloromethane. The dichloromethane solution 5 was evaporated to dryness and the residue was refluxed with 50 ml of a 2% methanolic potassium methylate solution for 2 h. The mixture was then allowed to stand at 0 ° C for 2 h, after which the precipitated (+) - vincamine crystals were filtered off, washed with two 10 ml portions of methanol and dried at 60 ° C. 13.7 g (65%) of the title compound were obtained.

Z 7 -7 ° C = + 41 ° (c = 1, pyridine).

Melting point: 234-235 ° C (chlorobenzene)

EXAMPLE II

15 (+) - vincamine

A mixture of 36.9 g (0.1 mol) (-) - 1cr-ethyl-13 - (2 * -methoxycarbonyl-2 * -hydroxyiminoethyl) -1,2,3,4,6,7,12, 12ba octahydroindolo / 2,3-a7quinolizine (Hungarian patent application 1753/81), 16.8 ml acetic acid, 250 ml water, 5.8 ml concentrated sulfuric acid and 75 g sodium pyrosulfite were stirred at 90 ° C for 7 h . After cooling, the pH of the mixture was adjusted to 9 with 60 ml of a concentrated aqueous ammonium hydroxide solution. The alkaline solution was extracted with 200 ml and then with 100 ml of dichloromethane. Dichloromethane was distilled from the combined dichloromethane extracts, 100ml of a 2% methanolic potassium methylate solution was added to the distillation residue, and the mixture was refluxed for 4h.

The reaction mixture was then cooled, left to stand at 0 ° C for 30 h, filtered and the solid washed with two 30 ml portions of methanol and then dried at 60 ° C. 26.6 g (75%) of the title compound were obtained.

Z = 7 ° = + 41 ° (c. -1, pyridine).

Melting point: 234-235 ° C (chlorobenzene).

The filtrate (mother liquor from epimerization) was evaporated to dryness, 16 ml of ethanol, 20 g of dry p-toluenesulfonic acid and 120 ml of toluene were added to the residue. The 8203768-6 mixture was heated to boiling and 80 ml of the solvent was distilled off. The mixture was then refluxed for 2 h. The reaction mixture was cooled to 10 ° C, 50 ml of toluene and 50 ml of water were added and the pH was adjusted to 9 with a concentrated aqueous ammonium hydroxide solution. The toluene layer was separated and the aqueous layer was extracted with 50 ml of toluene. The combined toluene solutions were dried over anhydrous sodium sulfate solid, filtered and the filtrate decolorized with 1 g Brockmann alumina. The solution was then concentrated to 20 ml, a solution of 0.6 g of potassium tert-butylate in 40 ml of ethanol was added and the mixture was refluxed for 1 h. The reaction mixture was evaporated to 20 ml, cooled to 10 ° C, and the precipitated crystals were filtered, washed with two 10 ml portions of ethanol and dried. 3.5 g (+) - apo-vincamic acid ethyl ester with a melting point of 145-147 ° C were obtained. Yield: 10% based on the starting material.

[Α = 141 ° (c = 1, chloroform).

EXAMPLE III

(+) - vincamine

A mixture of 36.9 g (0.1 mol) (+) - 1a-ethyl-13- (2'-methoxycarbonyl-2'-hydroxyiminoethyl) -1,2,3,4,6,7,12,12ba Octahydroindolo / 2,3-a7quinolizine (Hungarian patent application 1743/81), 16.8 ml acetic acid, 250 ml water, 15 ml concentrated sulfuric acid and 46.5 g sodium sulfite were stirred at 90 ° C for 6 h. After cooling, the pH was adjusted to 9 with 60 ml of concentrated sodium hydroxide aqueous solution and the alkaline solution was extracted with two 100 ml portions of dichloromethane. Dichloromethane was distilled from the combined dichloromethane extracts, 110ml of a 2% methanolic potassium methylate solution was added to the residue, and the mixture was refluxed for 4h. The reaction mixture was cooled to 0 ° C, 35 and the precipitated crystals were filtered off, washed with two 30 ml portions of methanol and dried at 60 ° C. 20.8 g (59%) of the title compound were obtained. Melting point: 234-235 ° C (chlorobenzene).

8203768 - 7 -

EXAMPLE IV

(+) - vincamine

In a 2 l enamelled autoclave, in a mixture of 50 g (-) - Ια-ethyl-lβ- (2'-methoxycarbonyl-2'-5-hydroxyiminoethyl) -1,2,3,4,6,7,12 i2ba-octahydroindolo / 2,3-a7-quinolizine (Hungarian patent application 1753/81), 82 g of sodium acetate, 700 ml of water and 15 ml of concentrated sulfuric acid introduced 64 g of sulfur dioxide gas, after which the autoclave was closed and at 80 h for 5 h -90 ° C was maintained under an overpressure of 0.2-0.3 atm. After cooling, the autoclave was opened, 130 ml of concentrated aqueous ammonium hydroxide solution was added to the reaction mixture and the alkaline solution was extracted with two 200 ml portions of dichloromethane. The combined dichloromethane layers were evaporated to dryness and the evaporation residue was refluxed with 150 ml of a 2% methanolic potassium methylate solution for 4 h. The mixture was cooled, and the precipitated crystals were filtered off, washed with two 30 ml portions of methanol and dried at 60 ° C. 29 g of 20 (60.5%) of the title compound were obtained.

Melting point: 234-235 ° C (chlorobenzene).

/ \ 7q ° = 42 ° (c = 1, pyridine).

EXAMPLE V

(+) - vincamic acid ethyl ester The procedure described in Example II was followed except that as a starting material 38.3 g (0.1 mol) (-) - 1a-ethyl-1B- (2-ethoxycarbonyl-) 2'-hydroxyiminoethyl) -1,2,3,4,6,7,12,12ba-octahydroindolo / 2,3-aquinololine (Hungarian patent application 1753/81) was used. The epimerization was performed with a corresponding amount of ethanolic potassium methylate solution. 27.4 g (74%) of the title compound were obtained.

Melting point: 238-240 ° C.

To the mother liquor of the epimerization was added 20 g of "35 dry p-toluenesulfonic acid and the mixture was evaporated to 50 ml. To the concentrated solution was added 150 ml of toluene, after which 75 ml of the solvent was distilled off, the interior temperature rose to 110 ° C.

8203768 - 8 -

The reaction mixture was then refluxed for 2 h and then cooled to 10 ° C, then 50 ml of toluene and 50 ml of water were added and the pH was adjusted to 9 with a concentrated aqueous ammonium hydroxide solution. The toluene layer was separated, the aqueous layer was extracted with 50 ml of toluene, and the combined toluene extracts were dried over solid anhydrous sodium sulfate, filtered and the filtrate was decolorized with 5 g of Brockmann alumina. The filtrate was then evaporated to 20 ml and 50 ml of ethanol were added to the residue, 25 ml of which were distilled off. The mother liquor was cooled to 10 ° C. The crystals precipitated were filtered off, washed with two 10 ml portions of ethanol and dried. 3.9 g (11%, based on the starting material) (+) - apovincamic acid ethyl ester were obtained. Melting point: 142 ° C.

EXAMPLE VI

(+) - trans-vineamine (33,16a) and (+) - trans-l4-epivincamine (3β, 16a).

A mixture of 51 g (0.15 mol) of (-) - trans-20 1α-ethyl-1 ¢ - (21-methoxycarbonyl-2'-hydroxyiminoethyl) -1,2,3,4,6,7,12 12i-octahydroindolo / 2,3-quinololine (Hungarian patent application 1753/81), 600 ml of water, 50 ml of acetic acid, 7.5 ml of concentrated sulfuric acid and 20 g of sodium pyrosulfite were stirred at 92 ° C for 2 h. A further 10 g portion of sodium pyrosulfite was added to the mixture, which was then stirred at 92 ° C for an additional 4 h. The solution was cooled to 20 ° C, then 200 ml of chloroform was added and the pH was adjusted to 9 with a 20% aqueous sodium hydroxide solution. After stirring for 1 min, the layers were separated and the aqueous layer was extracted with 100 ml of chloroform. The chloroform solution was dried over solid anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. 50 ml of methanol was added to the evaporation residue, and the mixture was heated to boiling for 2 min and then left at 0 ° C for 1 h. The precipitated crystals were filtered off, washed with three 20 ml portions of methanol and dried.

30 g of white crystalline material, 8203768, were obtained

V

- 9 - consisting of a mixture of (+) - trans-vincamine and (+) - trans-14-epivincamine *

The mixture was refluxed with 40 ml of chloroform for 2 min and then left at 0 ° C for 2 h. The precipitate was filtered off and washed with two 10 ml portions of chloroform at a temperature of 0 ° C. 15 g of a substance enriched with (+) - vincamine were obtained. The product was refluxed in 40 ml of chloroform, left at 0 ° C for 1 h and the precipitated material was filtered off, washed with cold chloroform and dried.

10 g (19%) of pure (+) - trans-vincamine (33.16a) were obtained. Melting point: 189-190 ° C.

L = + 89 ° (c = 1, chloroform).

The chloroform filtrates were combined, evaporated in vacuo and the residue was dissolved in 20 ml of chloroform, after which the solution was diluted with 60 ml of methanol and left at 0 ° C for 2 h. The precipitated crystals were filtered and washed with two 20 ml 10 ml portions of methanol. 12 g of a material enriched in (+) - trans-14-epivincamine were obtained. The substance was dissolved in 20 ml of hot chloroform, after which the solution was diluted with 50 ml of methanol and left at 0 ° C for 2 h. The precipitated crystals were filtered off, washed with two 5 ml portions of methanol and dried. 8 g (15%) (+) - trans-14-epivincamine with a. melting point of 167-168 ° C.

Z \ 7d ° = + 36.5 ° (c = 1, chloroform.

30 8203768

Claims (7)

A process for the preparation of racemic and optically active vincamic acid esters of the formula 1 of the formula sheet, wherein R and R independently represent 5 alkyl of 1-6 carbon atoms and 14 epimers thereof, characterized in: that an octahydroindolo / 2,3-a] quinolizine oxime ester of the formula I 2 2 of the formula sheet, wherein R and R have the meanings indicated above, is reacted with an aqueous solution of sulfuric acid or a salt thereof, at a temperature of 80-110 ° C and that the 14-epimer mixture obtained is epimerized or separated in a manner known per se and, if desired, the resulting racemic vincamic acid esters are cleaved in their antipodes. Process according to claim 1, characterized in that the reaction is carried out at a pH between 3.5 and 7. Process according to claim 1 or 2, characterized in that an octahydroindolo / 2,3-a7chino-1 2 "* 20 lizine oxime ester of formula 2, wherein R and R have the meanings according to claim 1, is reacted with a alkali metal pyrosulfite in water, optionally in the presence of an organic or mineral acid. 4. Process according to claim 1 or 2, characterized in that an octahydroindolo / 2,3-a / quino-1-2-lizine oxime ester of formula 2, wherein R and R have the meanings according to claim 1, is reacted with an alkali metal hydroxide or an alkali metal salt while supplying sulfur dioxide and optionally an organic or inorganic acid is present. A process according to claim 1 or 2, characterized in that an octahydroindolo / 2,3-a / quino-12-lizine oxime ester of formula 2, wherein R and R have the meanings according to claim 1, is reacted with sodium sulfite in water, if desired an organic or inorganic acid is present. 6. Process according to any one of claims 3-5, characterized in that acetic acid is used as organic 8203768 • f-11 acid or sulfuric acid as inorganic acid. A method according to claim 4, characterized in that sodium acetate is used as an alkali metal salt. \ 5 8203768